EP0464112A1 - Procede de preparation de derives de guanine substitues en position 9, et intermediaires utilises dans ledit procede. - Google Patents

Procede de preparation de derives de guanine substitues en position 9, et intermediaires utilises dans ledit procede.

Info

Publication number
EP0464112A1
EP0464112A1 EP90905442A EP90905442A EP0464112A1 EP 0464112 A1 EP0464112 A1 EP 0464112A1 EP 90905442 A EP90905442 A EP 90905442A EP 90905442 A EP90905442 A EP 90905442A EP 0464112 A1 EP0464112 A1 EP 0464112A1
Authority
EP
European Patent Office
Prior art keywords
amino
imidazole
carboxamide
thiocarbamoyl
treatment
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP90905442A
Other languages
German (de)
English (en)
Other versions
EP0464112B1 (fr
Inventor
Borge Alhede
Finn Priess Clausen
Jorgen Juhl-Christensen
Klaus K Mccluskey
Herbert Preikschat
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sandoz AS
Original Assignee
GEA Farmaceutisk Fabrik AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by GEA Farmaceutisk Fabrik AS filed Critical GEA Farmaceutisk Fabrik AS
Publication of EP0464112A1 publication Critical patent/EP0464112A1/fr
Application granted granted Critical
Publication of EP0464112B1 publication Critical patent/EP0464112B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/052—Imidazole radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals

Definitions

  • the present invention relates to a process for the preparation of 9-substituted guanine derivatives of the general formula I
  • R is C 1 -C 4 -alkyl optionally substituted with one or more hydroxy groups, or R is
  • Compounds of this type are therapeutically active compounds having an antiviral activity or are intermediates for the preparation of compounds of interest in gene technology.
  • guanosine can be prepared from 4-carboxamide-5-amino-1- ribofuranosyl imidazole by a process in three steps which involves condensation with carbodiimide derivatives, cyclization with PdO present and treatment with NH 4 OH.
  • This process is not attractive because it requires use of the toxic compound phosgene to prepare the carbodiimide derivatives, and because the cyclization and the subsequent treatment with NH 4 OH take a very long time.
  • the compound of formula I in which R is H can be prepared by a process in which the compound of formula II
  • R has the same meaning as in formula I is cyclized a) by treatment with a heavy metal salt of the group of Cu-, Ag-, Pb- and Hg-salts in an aqueous alkaline medium containing at least four equivalents of OH- ions at a temperature from about 0°C to the reflux temperature, or b) by treatment with a peroxy compound in an aqueous alkaline medium at a temperature of about 0-30°C, whereafter I is isolated by treatment with acid and, if desired, is converted into a salt.
  • R is C 1 -C 4 -alkyl optionally substituted with one or more hydroxy groups, or R is benzyl, ribosyl, 2'-deoxyribosyl or (CH 2 ) n -OR 1 , where n is 1 or 2, and R 1 is CH 2 CH 2 or
  • the starting materials, of formula III can be prepared by reaction of 1-substituted 5-amino-1H-imidazole-4-carboxamides of the formula IV
  • R has the same meaning as in formula I and in which hydroxyl groups, if any, in R may be acylated, with acylisothiocyanate and subsequent hydrolysis to remove the N-acyl group and any other acyl groups.
  • the compounds of formula IV can be prepared by alkylation of the known compound 5-amino-1H-imidazole-4-carboxamide in a known manner.
  • the process according to the invention in variant a) is preferably carried out using a copper salt as the heavy metal salt.
  • a copper salt as the heavy metal salt.
  • the process in variant a) is advantageously carried out in the way that the aqueous alkaline medium is provided with an alkali metal hydroxide, preferably sodium or potassium hydroxide.
  • an alkali metal hydroxide preferably sodium or potassium hydroxide.
  • the process according to the invention in variant b) is preferably carried out using hydrogen peroxide as the peroxy compound and in the presence of tungstate ions as a catalyst.
  • 5-(N'-benzoylthiocarbamoyl)amino-1-ethyl-1H-imidazole-4- carboxamide was prepared in a similar manner from 5-amino- 1-ethyl-1H-imidazole 4-carboxamide, mp. 178-180°C.
  • 5-(N'-benzoylthiocarbamoyl)amino-1-benzyl-1H-imidazole-4- carboxamide was prepared in a similar manner from 5-amino- 1-benzyl-1H-imidazole-4-carboxamide, mp. 181-182.5oC. 1-[(2-Hydroxyethoxy)methyl]-5-(thiocarbamoyl)amino-1H- imidazole-4-carboxamide.
  • Acetyl chloride (1.6 g, 21 mM) was, under N 2 , added dropwise to a solution of ammonium thiocyanate (1.6 g, 21 mM) in acetone (30 ml) at 25oC in the course of 5 minutes. After reflux for 15 minutes it was cooled to 20oC, and the formed ammonium chloride was filtered off and washed with acetone (10 ml).
  • 9-Ethylguanine was prepared in a similar manner from 1- ethyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide, mp. >300oC.
  • 9-(1-Propyl)guanine was prepared in a similar manner from 1-(1-propyl)-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide, mp . >300oC. 13 C-NMR(DMSO-d 6 ) ⁇ ppm: 156.8; 153.3; 151.0; 137.4; 116.5; 44.2; 22.7; 10.8.
  • Example 9 9 -Benzylguanine 1-Benzyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide (2.75 g, 10.0 mM) and sodium tungstate (0.1 g) were suspended in 6 N sodium hydroxide (20 ml) at 5oC. 35% hydrogen peroxide (4.0 ml, 44 mM) was added dropwise at 5-15oC over 30 minutes. Water (60 ml) was added to the resulting reaction mixture. After stirring for 1 hour in an ice bath pH was adjusted to 5 with hydrochloric acid. The formed product was filtered off, washed with water and dried. Hereby was isolated 1.30 g (54%) of the title compound as a white powder. HPLC indicated about 98% purity. The product had the same physical data as the product of example 4.
  • 9-Methylguanine 9-Methylguanine was prepared In a similar manner from 1- methyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide. The product had the same physical data as the product of example 1.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Biotechnology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un procédé de préparation de dérivés de guanine substitués en position 9, selon la formule générale (I), dans laquelle R représente alcoyle C1-C4 facultativement remplacé par un ou plusieurs groupes hydroxy, où R représente (alpha), benzyle, ribosyle, 2'-désoxyribosyle ou (CH2)n-OR1 où n représente 1 ou 2, et R1 représente CH2CH2OH ou (beta), ou leurs sels, dans lequel un 5-(thiocarbamoyle) amino-1H-imidazole-4-carboxamide substitué en position 1, de la formule générale (III), dans laquelle R est défini comme dans la formule (I), est cyclisé: a) par traitement à l'aide d'un sel de métal lourd du groupe composé de sels de Cu, Ag, Pb et Hg dans un milieu alcalin aqueux contenant au moins quatre équivalents d'ions OH-, à température comprise entre environ 0°C et la température de reflux ou b) par traitement à l'aide d'un composé peroxy dans un milieu alcalin aqueux à une température comprise entre environ 0 et 30°C, après quoi (I) est isolé par traitement à l'acide, et si désiré, est transformé en un sel. L'invention comprend en outre des intermédiaires utilisés dans la préparation des composés précités.
EP90905442A 1989-03-20 1990-03-19 Procede de preparation de derives de guanine substitues en position 9, et intermediaires utilises dans ledit procede Expired - Lifetime EP0464112B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DK1354/89 1989-03-20
DK135489A DK135489D0 (da) 1989-03-20 1989-03-20 Fremgangsmaade til fremstilling af 9-substituerede guaninderivater og mellemprodukter til brug ved fremgangsmaaden
PCT/DK1990/000077 WO1990011283A1 (fr) 1989-03-20 1990-03-19 Procede de preparation de derives de guanine substitues en position 9, et intermediaires utilises dans ledit procede

Publications (2)

Publication Number Publication Date
EP0464112A1 true EP0464112A1 (fr) 1992-01-08
EP0464112B1 EP0464112B1 (fr) 1994-10-05

Family

ID=8103930

Family Applications (1)

Application Number Title Priority Date Filing Date
EP90905442A Expired - Lifetime EP0464112B1 (fr) 1989-03-20 1990-03-19 Procede de preparation de derives de guanine substitues en position 9, et intermediaires utilises dans ledit procede

Country Status (28)

Country Link
US (1) US5223619A (fr)
EP (1) EP0464112B1 (fr)
KR (1) KR0142098B1 (fr)
AR (1) AR245719A1 (fr)
AT (1) ATE112568T1 (fr)
BG (1) BG60590B1 (fr)
BR (1) BR9007230A (fr)
CA (1) CA2047217A1 (fr)
CS (1) CS9001365A3 (fr)
DD (1) DD293116A5 (fr)
DE (1) DE69013146T2 (fr)
DK (2) DK135489D0 (fr)
ES (1) ES2061023T3 (fr)
FI (1) FI97387C (fr)
GE (1) GEP19971014B (fr)
GR (1) GR1001096B (fr)
HR (1) HRP920907B1 (fr)
HU (1) HU206715B (fr)
IE (1) IE62042B1 (fr)
LT (1) LT3183B (fr)
LV (1) LV10455B (fr)
NO (1) NO178497C (fr)
PL (1) PL163313B1 (fr)
RO (1) RO109737B1 (fr)
RU (2) RU2090566C1 (fr)
SI (1) SI9010545A (fr)
WO (1) WO1990011283A1 (fr)
YU (1) YU47343B (fr)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1264599B1 (it) * 1993-06-14 1996-10-04 Solar Chem Sa Processo per la sintesi della 9-(2-idrossietossimetil)- guanina
GB9520364D0 (en) * 1995-10-05 1995-12-06 Chiroscience Ltd Compouundds
DE69922009T2 (de) * 1998-07-23 2005-04-07 Fujisawa Pharmaceutical Co., Ltd. Imidazolverbindungen und ihre verwendung als adenosindeaminase-inhibitoren
US6860928B2 (en) 2002-09-04 2005-03-01 Xerox Corporation Alkylated urea and triaminotriazine compounds and phase change inks containing same
US6872243B2 (en) 2002-09-04 2005-03-29 Xerox Corporation Phase change inks containing gelator additives
US6761758B2 (en) 2002-09-04 2004-07-13 Xerox Corporation Alkylated tetrakis(triaminotriazine) compounds and phase change inks containing same
US6811595B2 (en) 2002-09-04 2004-11-02 Xerox Corporation Guanidinopyrimidinone compounds and phase change inks containing same
US7144450B2 (en) 2004-12-04 2006-12-05 Xerox Corporation Phase change inks containing trans-1,2-cyclohexane bis(urea-urethane) compounds
US7220300B2 (en) 2004-12-04 2007-05-22 Xerox Corporation Phase change inks containing bis(urea-urethane) compounds
US7314949B2 (en) 2004-12-04 2008-01-01 Xerox Corporation Trans-1,2-cyclohexane bis(urea-urethane) compounds
US7317122B2 (en) 2004-12-04 2008-01-08 Xerox Corporation Curable trans-1,2-cyclohexane bis(urea-urethane) compounds
US7153349B2 (en) 2004-12-04 2006-12-26 Xerox Corporation Phase change inks containing curable trans-1,2-cyclohexane bis(urea-urethane) compounds
US7560587B2 (en) 2004-12-04 2009-07-14 Xerox Corporation Bis[urea-urethane] compounds
SI3062949T2 (sl) 2013-10-29 2023-08-31 Swep International Ab Postopek trdega lotanja ploščatega izmenjevalnika toplote s pomočjo s sitotiskom nanešenega lota
CN115504977B (zh) * 2022-09-23 2024-02-09 海南锦瑞制药有限公司 更昔洛韦的制备方法及注射用更昔洛韦的制备方法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56152437U (fr) * 1980-04-14 1981-11-14
US4451478A (en) * 1982-03-12 1984-05-29 Newport Pharmaceuticals International, Inc. Imidazole compounds
US4602089A (en) * 1982-03-12 1986-07-22 Newport Pharmaceuticals, Inc. Process for preparing purine compounds
JPS6055071B2 (ja) * 1982-04-16 1985-12-03 四国化成工業株式会社 イミダゾリル琥珀酸化合物および該化合物を用いるエポキシ樹脂硬化方法
HUT36464A (en) * 1983-05-24 1985-09-30 Newport Pharmaceuticals Process for producing erythro-4-amino-3-/2-hydroxy-3-alkyl/-imidazol-5-carboxamide
EP0219838A3 (fr) * 1985-10-22 1988-04-06 Takeda Chemical Industries, Ltd. Nucléosides de purine carbocycliques, leur préparation et leur utilisation
MY101126A (en) * 1985-12-13 1991-07-31 Beecham Group Plc Novel compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9011283A1 *

Also Published As

Publication number Publication date
RO109737B1 (ro) 1995-05-30
NO913686L (no) 1991-09-19
GR1001096B (el) 1993-04-28
HRP920907A2 (hr) 1994-04-30
LV10455A (lv) 1995-02-20
NO178497B (no) 1996-01-02
IE62042B1 (en) 1994-12-14
KR0142098B1 (ko) 1998-06-01
CS275359B2 (en) 1992-02-19
DK0464112T3 (da) 1995-03-13
RU2042668C1 (ru) 1995-08-27
HUT59141A (en) 1992-04-28
YU47343B (sh) 1995-01-31
WO1990011283A1 (fr) 1990-10-04
GEP19971014B (en) 1997-04-18
BG95145A (bg) 1993-12-24
DE69013146T2 (de) 1995-02-16
PL163313B1 (pl) 1994-03-31
LT3183B (en) 1995-03-27
BG60590B1 (en) 1995-09-29
IE900994L (en) 1990-09-20
HU902874D0 (en) 1991-12-30
EP0464112B1 (fr) 1994-10-05
GR900100212A (en) 1990-07-31
DK135489D0 (da) 1989-03-20
LV10455B (en) 1995-08-20
CS9001365A3 (en) 1992-02-19
YU54590A (sh) 1992-12-21
NO178497C (no) 1996-04-10
SI9010545A (en) 1997-08-31
DD293116A5 (de) 1991-08-22
FI97387B (fi) 1996-08-30
ATE112568T1 (de) 1994-10-15
HRP920907B1 (en) 1998-06-30
BR9007230A (pt) 1992-02-25
LTIP297A (en) 1994-08-25
FI97387C (fi) 1996-12-10
KR920701208A (ko) 1992-08-11
AR245719A1 (es) 1994-02-28
CA2047217A1 (fr) 1990-09-21
DE69013146D1 (de) 1994-11-10
NO913686D0 (no) 1991-09-19
RU2090566C1 (ru) 1997-09-20
FI914418A0 (fi) 1991-09-19
US5223619A (en) 1993-06-29
HU206715B (en) 1992-12-28
ES2061023T3 (es) 1994-12-01

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